Several transport pathways are involved in the regulation of cell volume and ion content in the human erythrocyte. Studies of these pathways have shown that K-Cl contransport and the Ca-gated K channel (Gardos channel) play an important role in the dehydration of sickle erythrocytes. Therapeutic strategies based on the specific blockade of these pathways have been tested in transgenic sickle mice and in patients with sickle cell disease, using oral Mg pidolate to inhibit K-Cl cotransport and oral clotrimazole to inhibit the Gardos channel. Studies on the erythrocyte Na-H (Na-Li) exchanger have uncovered an important role for insulin and blood pressure in mediating the activity of this pathway. These findings explain the reports of abnormal Na-Li exchange in diabetic nephropathy and essential hypertension. Targeted mutagenesis of the anion exchanger protein band 3 in mice has demonstrated that absence of this protein is compatible with life and leads to severe hemolytic anemia, normal assembly of the cytoskeleton, and reduced mechanical stability of the erythrocyte. Identification of the molecular identity of all the major erythrocyte transporters is imminent and will provide the bases for future studies of these proteins in the normal and abnormal erythrocyte.